Efficacy And Safety Of Macitentan Tadalafil Fixed Dose Combination In Pulmonary Arterial Hypertension: Results From The Randomized Controlled Phase III A DUE Study

Dr. Cansu Öztürk

Published in Congress: ACC 2023

Background:
In pulmonary arterial hypertension (PAH), macitentan 10 mg and tadalafil 40 mg are recommended as combination therapy in most newly diagnosed and followed-up patients. Therefore, macitentan 10 mg + tadalafil 40 mg fixed dose combination (FDC) as a single tablet may offer a simplified treatment approach.

Objective:
To compare the safety and efficacy of macitentan/tadalafil combination therapy versus macitentan and tadalafil monotherapies in patients with PAH.

Methods:
A DUE study is a prospective, multicenter, double-blind, randomized, active-controlled, adaptive phase 3 study. The study consisted of a total of 187 people with a mean age of 51, with a female rate of 78%. Follow-up period is 16 weeks. Inclusion criteria were adult patients with World Health Organization (WHO) functional class 2 or 3 (those who were untreated or used a fixed dose ERA or PDE5i for ³3 months). The rate of idiopathic pulmonary hypertension is 50% and the duration of diagnosis of PAH is 2.5 years.
The primary efficacy endpoint was change in PVR. Secondary efficacy endpoints were; change in 6MWD, change in PAH-SYMPACT score, absence of worsening in WHO functional class. Safety and tolerability were monitored throughout the study.

Results:
The primary endpoint for macitentan and the combination was the percent change in pulmonary vascular resistance (PVR) from baseline at 6 weeks: -23 vs -45% (p ≤ 0.0001).
For tadalafil and the combination: -22 vs. -44% (p ≤ 0.0001).
Secondary results:

• Change from baseline in 6-minute walk for macitentan and combination at 16 weeks: 38.5 versus 52.9 m (p = 0.38)
• For tadalafil and combination: 15.9 vs. 43.4 (p = 0.06)

Conclusion:
In the Macitentan/Tadalafil fixed dose combination (FDC), has been very significant and markedly improvement in PVR as the primary endpoint, compared to macitentan and tadalafil monotherapies. A clinically significant improvement was observed in favor of M/T FDC in 6MWD. The tolerability of the M/T FDC has been well and its safety is consistent with the safety profile of monotherapies.

Interpretations:
Study result; demonstrated that a fixed dose combination therapy of 10 mg macitentan + 40 mg tadalafil daily was superior to either agent as monotherapy in reducing PVR at 6 weeks in patients with PAH. The side-effect profile was similar to monotherapies. But the study was too small to assess clinical endpoints. These data suggest an emerging role for combination therapy in this patient population. A DUE trial supports M/T FDC as initial dual combination therapy and single tablet combination therapy for rapid escalation, in accordance with the ESC/ERS 2022 guidelines for the use of dual combination therapy in PAH.